Abstract
The increase in resistant bacterial strains necessitates the identification of new antimicrobial molecules. Antimicrobial peptides (AMPs) are an attractive option because of evidence that bacteria cannot easily develop resistance to AMPs. The peptaibols, a class of naturally occurring AMPs, have shown particular promise as antimicrobial drugs, but their development has been hindered by their mechanism of action not being clearly understood. To explore how peptaibols might interact with membranes, circular dichroism, vibrational circular dichroism, linear dichroism, Raman spectroscopy, Raman optical activity, neutron reflectivity and molecular dynamics simulations have been used to study a small library of peptaibol mimics, the Aib‐rich peptides. All the peptides studied quickly partitioned and oriented in membranes, and we found evidence of chiral interactions between the phospholipids and membrane‐embedded peptides. The protocols presented in this paper open new ground by showing how chiro‐optical spectroscopies can throw light on the mechanism of action of AMPs.
Highlights
The activity of antimicrobial peptides (AMPs) usually depends upon their ability to bind to a cell membrane and their subsequent interactions with it
Circular dichroism: Peptides (S)-2 and (R)-2 have a similar hydrophobic surface with the same terminal functionalisation as (S)-1 and (R)-1 but with no N-terminal aromatic amino acid
There is a sign change of the circular dichroism (CD) band at 220 nm from (S)-2 in acetonitrile compared to (S)-2 in lipid. It is commonly observed for the 220 nm CD band in 310 helical Aib foldamers to change in different solvents or even with concentration
Summary
The activity of antimicrobial peptides (AMPs) usually depends upon their ability to bind to a cell membrane and their subsequent interactions with it. Studies in solution have demonstrated that Aib foldamers weakly self-associate in chloroform solution, a solvent that is often assumed to mimic the membrane environment.[6,26] X-ray investigations on the racemic mixtures of both 1 and 2 showed that in the solid state the peptides adopt a 310 helical conformation.[18,27] 8-Hydroxypyrenetrisulfonate (HPTS) studies of the ionophoric activity of the peptide 1 in EYPC/cholesterol vesicles showed that at concentrations of 60 μM (25 : 2 lipid/ peptide), the peptide allowed the leakage of ions and dye through the membrane without disrupting it This ionophoric activity was found to be higher for the racemate compared to the enantiopure peptides.[18] Based on these results it has been suggested that the peptides exhibit membrane activity through an “amyloid-like” mechanism with the formation of heterogeneous populations of aggregate that can span the membrane. ChemBioChem 2021, 22, 1656 – 1667 www.chembiochem.org these processes without the need to alter (label) the structure of these small peptides
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